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Moderate Hypoxia Potentiates Interleukin-1&bgr; Production in Activated Human Macrophages

Moderate Hypoxia Potentiates Interleukin-1&bgr; Production in Activated Human Macrophages Clinical Track Moderate Hypoxia Potentiates Interleukin-1β Production in Activated Human Macrophages Eduardo J. Folco, Galina K. Sukhova, Thibaut Quillard, Peter Libby Rationale: Inflammation drives atherogenesis. Animal and human studies have implicated interleukin-1β (IL- 1β) in this disease. Moderate hypoxia, a condition that prevails in the atherosclerotic plaque, may conspire with inflammation and contribute to the evolution and complications of atherosclerosis through mechanisms that remain incompletely understood. Objective: This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1β production in activated human macrophages. Methods and Results: Our results demonstrated that hypoxia enhances pro-IL-1β protein, but not mRNA, expression in lipopolysaccharide-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1β to autophagic degradation, thus prolonging its half-life and promoting its intracellular accumulation. Furthermore, hypoxia increased the expression of NLRP3, a limiting factor in NLRP3 inflammasome function, and augmented caspase-1 activation in lipopolysaccharide-primed macrophages. Consequently, hypoxic human macrophages secreted higher amounts of mature IL-1β than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1β localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Circulation Research Wolters Kluwer Health

Moderate Hypoxia Potentiates Interleukin-1&bgr; Production in Activated Human Macrophages

Libby, Peter
Circulation Research , Volume 115 (10) – Oct 1, 2014
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References (54)

Copyright
© 2014 American Heart Association, Inc.
ISSN
0009-7330
eISSN
1524-4571
DOI
10.1161/CIRCRESAHA.115.304437
pmid
25185259
Publisher site
See Article on Publisher Site

Abstract

Clinical Track Moderate Hypoxia Potentiates Interleukin-1β Production in Activated Human Macrophages Eduardo J. Folco, Galina K. Sukhova, Thibaut Quillard, Peter Libby Rationale: Inflammation drives atherogenesis. Animal and human studies have implicated interleukin-1β (IL- 1β) in this disease. Moderate hypoxia, a condition that prevails in the atherosclerotic plaque, may conspire with inflammation and contribute to the evolution and complications of atherosclerosis through mechanisms that remain incompletely understood. Objective: This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1β production in activated human macrophages. Methods and Results: Our results demonstrated that hypoxia enhances pro-IL-1β protein, but not mRNA, expression in lipopolysaccharide-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1β to autophagic degradation, thus prolonging its half-life and promoting its intracellular accumulation. Furthermore, hypoxia increased the expression of NLRP3, a limiting factor in NLRP3 inflammasome function, and augmented caspase-1 activation in lipopolysaccharide-primed macrophages. Consequently, hypoxic human macrophages secreted higher amounts of mature IL-1β than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1β localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor

Journal

Circulation Research – Wolters Kluwer Health

Published: Oct 1, 2014

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